Surface antigens of Toxoplasma gondii: variations on a theme

Lekutis, Christine; Ferguson, David J. P.; Grigg, Michael E.; Camps, Manel; Boothroyd, John C.

doi:10.1016/s0020-7519(01)00261-2

Cited by 210 publications

(167 citation statements)

References 49 publications

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“…In particular, SAG1 is a highly immunogenic prototypic member of the family expressed on the invasive tachyzoite, predicted to bind polyanionic ligands and presumed to serve as an immune decoy facilitating chronic infection; anti-SAG1 antibodies reduce parasite invasion in vitro, and SAG1-null parasites showed less virulence in mice experiments (39,(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Structure of thePlasmodium6-cysteine s48/45 domain

Arredondo

Cai²,

Takayama³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

107

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The s48/45 domain was first noted in Plasmodium proteins more than 15 y ago. Previously believed to be unique to Plasmodium , the s48/45 domain is present in other aconoidasidans. In Plasmodium , members of the s48/45 family of proteins are localized on the surface of the parasite in different stages, mostly by glycosylphosphatydylinositol-anchoring. Members such as P52 and P36 seem to play a role in invasion of hepatocytes, and Pfs230 and Pfs48/45 are involved in fertilization in the sexual stages and have been consistently studied as targets of transmission-blocking vaccines for years. In this report, we present the molecular structure for the s48/45 domain corresponding to the C-terminal domain of the blood-stage protein Pf12 from Plasmodium falciparum , obtained by NMR. Our results indicate that this domain is a β-sandwich formed by two sheets with a mixture of parallel and antiparallel strands. Of the six conserved cysteines, two pairs link the β-sheets by two disulfide bonds, and the third pair forms a bond outside the core. The structure of the s48/45 domain conforms well to the previously defined surface antigen 1 (SAG1)-related-sequence (SRS) fold observed in the SAG family of surface antigens found in Toxoplasma gondii . Despite extreme sequence divergence, remarkable spatial conservation of one of the disulfide bonds is observed, supporting the hypothesis that the domains have evolved from a common ancestor. Furthermore, a homologous domain is present in ephrins, raising the possibility that the precursor of the s48/45 and SRS domains emerged from an ancient transfer to Apicomplexa from metazoan hosts.

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Section: Discussionmentioning

confidence: 99%

Structure of thePlasmodium6-cysteine s48/45 domain

Arredondo

Cai²,

Takayama³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

107

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“…The only other treatment known to enhance invasion is incubation of the parasites with spent culture supernatant containing the rhoptry protein, ROP1 (31). Parasites engineered to lack the major glycosylphosphatidylinositol-anchored surface protein, SAG1, also appear to invade fibroblasts with faster kinetics than wild-type parasites (32). The mechanism(s) underlying these effects is unknown.…”

Section: )mentioning

confidence: 99%

A small-molecule approach to studying invasive mechanisms of Toxoplasma gondii

Carey

Westwood

Mitchison

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

130

163

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Toxoplasma gondii is the most common protozoan parasite of humans. Infection with T. gondii can lead to life-threatening disease as a result of repeated cycles of host cell invasion, parasite replication, and host cell lysis. Relatively little is known about the invasive mechanisms of T. gondii and related parasites within the Phylum Apicomplexa (including Plasmodium spp., the causative agents of malaria), due to difficulties associated with studying genes essential to invasion in haploid obligate intracellular organisms. To circumvent this problem, we have developed a highthroughput microscope-based assay, which we have used to screen a collection of 12,160 structurally diverse small molecules for inhibitors of T. gondii invasion. A total of 24 noncytotoxic invasion inhibitors were identified. Secondary assays demonstrated that different inhibitors perturb different aspects of invasion, including gliding motility, secretion of host cell adhesins from apical organelles (the micronemes), and extension of a unique tubulinbased structure at the anterior of the parasite (the conoid). Unexpectedly, the screen also identified six small molecules that dramatically enhance invasion, gliding motility, and microneme secretion. The small molecules identified here reveal a previously unrecognized complexity in the control of parasite motility and microneme secretion, and they constitute a set of useful probes for dissecting the invasive mechanisms of T. gondii and related parasites. Small-molecule-based approaches provide a powerful means to address experimentally challenging problems in host-pathogen interaction, while simultaneously identifying new potential targets for drug development. N early one-third of all deaths in the world today are caused by infectious disease. The development of new preventative and therapeutic strategies relies on an improved understanding of the interaction between pathogens and their hosts. In many pathogenic systems, this presents a formidable experimental challenge, because standard genetic tools are either rudimentary or unavailable. Biochemical, genomic, and other approaches exist, but these lack the assumption-free power of a genetic screen.An alternative nongenetic approach to studying mechanisms of host-pathogen interaction involves screening large structurally diverse collections of small molecules for those that disrupt the interaction. Once identified, the small molecules (or their derivatives) are used to determine the cellular components that function in the process (reviewed in refs. 1-3). The approach relies on the demonstrated ability of many small molecules to interact specifically with their targets (e.g., ref. 4). As with classical forward genetic screens, the approach is assumptionfree: by sampling large unbiased collections of structurally diverse small molecules, the screen ''selects'' structures that perturb the process under study. Such phenotype-based highthroughput screening has recently gained momentum in the academic setting due to technological advances and the av...

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“…Glycosylphosphatidylinositol (GPI)-anchored proteins dominate the surface of the T. gondii tachyzoite [308,309] , and GPI synthesis is an essential process for viability of the parasite [310,311] . GPI from tachyzoites induced TNF-α generation in macrophages via the activation of the transcription factor NF-κB [312] .…”

Section: T Gondii Infectionmentioning

confidence: 99%

Possible Pivotal Role of Latent Chronic T. gondii Infection in the Pathogenesis of Atherosclerosis

Prandota

2017

Journal of Cardiology and Therapy

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Surface antigens of Toxoplasma gondii: variations on a theme

Cited by 210 publications

References 49 publications

Structure of thePlasmodium6-cysteine s48/45 domain

Structure of thePlasmodium6-cysteine s48/45 domain

A small-molecule approach to studying invasive mechanisms of Toxoplasma gondii

Possible Pivotal Role of Latent Chronic T. gondii Infection in the Pathogenesis of Atherosclerosis

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